Vertebral fractures (VF) afflict more than 25% of people over age 50, and their burden is growing. Current approaches for estimating VF risk, which rely heavily on measurement of the average bone mineral density (BMD) in the vertebra, are known to be insufficient, but the search for better diagnostics is hindered by poor understanding of the pathogenesis of VF. Increasing evidence suggests that the risk, mechanisms, and outcomes of VF depend critically on the interaction of tissues near the interface between the vertebra and the intervertebral disc. This endplate region is defined as the cartilage endplate (CEP), the bony endplate (BEP), and the subchondral trabecular bone (STB). The disc mediates how the net force borne by a given vertebra is distributed over the surface of the endplate (?endplate loading?), and the endplate region mediates how this force distribution is transferred to the rest of the vertebra. The mechanical behaviors of the disc and endplate region are therefore expected to affect when and how the vertebra fails. Indeed, we have found that VF in elderly vertebrae commonly initiate within the endplate region, and that the way this region fails is influenced by not only the microstructure of this region but also the extent of degeneration in the adjacent disc. Moreover, recent data suggest that the mechanical behavior of the endplate region may change with aging and disc degeneration in ways that are not well predicted by the average BMD of the vertebra. These collective findings reveal a paradigm in which delineation of the biomechanical interactions between the endplate region and disc holds an important key to identifying risk factors for VF and, consequently, to reducing the incidence and burden of VF. As such, the overall goal of this project is to define how degeneration and aging of the disc and endplate region influence the mechanisms of VF. Aim #1 will quantify the dependence of endplate loading on disc degeneration and will use non-invasively obtained estimates of endplate loading to develop accurate, patient-specific, finite element (FE) simulations of VF. This Aim will capitalize on recent advances in magnetic resonance imaging (MRI)-based assessments of the disc to achieve a novel integration of the state-of-the-art in clinically feasible FE models of the disc and vertebra. Aim #2 will address the current paucity of data on the biomechanics of the endplate region. Using mechanical testing, FE modeling and biochemical assays, we will identify the extent to which properties such as the brittleness of the BEP, strength of the STB, and stiffness of the CEP change with age and disc degeneration. Aim #3 will focus on the way in which the endplate region fails during VF. Motivated by clinical and pre-clinical observations that disc health declines more rapidly following VFs that involve fracture of the BEP, as opposed to those that involve failure of only the STB, we will use both experiment and large-scale FE models to identify characteristics of the disc and endplate region that are associated with BEP fracture. Altogether, these three Aims constitute a mechanistic, innovative, and interdisciplinary approach that will enable a step change in the understanding, prevention, and treatment of VF.